Safety and Immunogenicity of a Tetravalent Live-attenuated Dengue Vaccine in Flavivirus Naive Children

Abstract

A live-attenuated tetravalent dengue virus (DENV) vaccine candidate has been well tolerated and immunogenic in healthy, US flavivirus naive adult volunteers. We conducted a pilot, safety, and immunogenicity trial of the vaccine candidate in healthy Thai children (6-7 years of age) to prepare for its eventual evaluation in Thai infants. In an uncontrolled, open clinical trial, the investigational vaccine was administered on study Days 0 and 180 to seven volunteers residing in Bangkok without neutralizing antibodies to DENV1-4 or to Japanese encephalitis virus (JEV). Clinical and laboratory safety assessments were completed during the 30 days after each vaccine dose, and immunogenicity was determined at Day 30. In this study, the vaccine was well tolerated with no serious adverse events or alert laboratory values. One volunteer experienced fever (38.2 degrees C, < 2 days) and associated DENV4 vaccine viremia 7 days after Dose 2. One month after Dose 2, six volunteers in the per-protocol analysis exhibited a tetravalent neutralizing antibody response with DENV1-4 geometric mean titers of 55, 475, 350, and 171, respectively. Ten weeks (~75 days) after Dose 2, five of the six volunteers continued to exhibit a tetravalent neutralizing antibody profile; one volunteer's DENV4 PRNT50 titer fell below the assay cut-off (29 --> < 10); (clinicaltrials.gov NCT00384670).

Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine in Flavivirus-Naive Infants

“…On each of the days that the DENV vaccine was formulated, retained samples of tetravalent product were frozen at −70°C, subsequently transported to WRAIR on dry ice, and returned to −70°C storage until thawed for potency testing using an immunofocus assay (IFA) as previously described. 12 Control vaccines. Varicella ( Varilrix ; GSK, Rixensart, Belgium) and H. influenzae type B ( Hiberix ; GSK, Rixensart, Belgium) vaccines(0.5-mL dose vial) were used as control vaccines for DENV vaccine doses 1 and 2, respectively.…”

“…12 After a review of medical history and physical examination (subjects were to be in good general health), screening tests included a complete blood count (CBC with white blood cell differential and platelet count), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B surface antigen, antibody to human immunodeficiency virus (HIV), and antibody to hepatitis C virus. Those with normal test results were further screened to exclude those with pre-existing antibody to DENV-1, -2, -3, or -4 or Japanese encephalitis virus (JEV) by hemagglutination inhibition (HAI) and 50% plaque reduction neutralization test (PRNT 50 ).…”

“…Thirty days after dose 2, 100% of the cohort had seroconverted to all DENV serotypes, with an observed boost in GMT for each DENV serotype (DENV-1, from less than 10 to 55; DENV-2, from 16 to 475; DENV-3, from 6 to 350; DENV-4, from 30 to 171). 12 Herein, we report the reactogenicity, safety and immunogenicity profile of the DENV vaccine candidate administered as two doses to flavivirus-naive Thai subjects aged 12 to 15 months. These subjects are being followed to assess long-term persistence of anti-DENV neutralizing antibodies and evaluate the safety and reactogenicity of a booster dose administered 3 years after primary vaccination (to be published separately).…”

“…8,9 The Walter Reed Army Institute of Research (WRAIR) and GlaxoSmithKline Biologicals (GSK) have developed a live-attenuated tetravalent DENV vaccine candidate to protect children and adults against dengue. [10][11][12] The vaccine candidate comprises four monovalent live virus strains representing each of the four serotypes attenuated by serial passage in primary dog kidney (PDK) cells ( Table 1 ). A well-tolerated and immunogenic formulation of the DENV vaccine candidate was identified in a phase 2 trial conducted in US adult volunteers.…”

“Current Dengue Vaccine Status”

“…A single formulation was advanced for testing in flavivirus-naïve toddlers and children in Thailand. Two vaccine doses administered on a 0 and 6 month schedule were well tolerated and immunogenic [46,47]. A third dose of vaccine in the Thai studies demonstrated no sustainable immunogenicity impact (Thomas, S., personal communication).…”